We recently observed that sera from patients with systemic lupus erythematosus (SLE) and other autoimmune and connective-tissue-disorders frequently contain lymphocytotoxic antibodies. We have planned prospective clinical studies to examine possible roles which such antibodies against cell-surface-antigens may plan in the pathogenesis of SLE. Since SLE sera are cytotoxic to lymphocytes from a large number of normal persons, we will attempt to determine whether the broad reactivity is due to an unusual immunologic responsiveness in SLE to normally present tissue antigens, or whether patients with SLE, possibly as a result of virus infection or other yet unknown events, develop neoantigens on their cell surfaces. Lymphocytes from SLE patients and their families will be examined by histocompatibility testing (tissue typing) in order to exclude the possibility that the neoantigens are inherited. The presence and significance of antibodies bound to lymphocyte surfaces will be studied using an antiglobulin test and by measuring quantitatively the uptake of isotopically labeled antibodies, using new procedures recently developed in our laboratory. Ultimately, a clearer understanding of the mechanisms underlying the pathogenesis of SLE may allow development of specific methods of treatment which will be more satisfactory than those available today.